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Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis.
Ma, Jingyi; Eadie, Kimberly; Schippers, Marij; Fahal, Ahmed; Laleu, Benoît; Verbon, Annelies; van de Sande, Wendy W J.
Afiliación
  • Ma J; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
  • Eadie K; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
  • Schippers M; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
  • Fahal A; Mycetoma Research Centre, Khartoum 1115, Sudan.
  • Laleu B; MMV Medicines for Malaria Venture, 1215 Geneva, Switzerland.
  • Verbon A; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
  • van de Sande WWJ; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
Int J Mol Sci ; 25(11)2024 Jun 05.
Article en En | MEDLINE | ID: mdl-38892422
ABSTRACT

OBJECTIVES:

Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma.

METHODS:

A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae.

RESULTS:

Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group.

CONCLUSION:

MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Madurella / Micetoma / Antifúngicos Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Madurella / Micetoma / Antifúngicos Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos